Strained intermediates have been involve as playing a crucial role in the conversion of the binding energy between enzymes and substrates to lowering the activation energy of the catalyzed reaction. In spite of the central role these intermediates may play, they have rarely been spectroscopically observed or the degree of strain quantified. Strain can by identified by changes in the vibrations spactrum of the bound substrate. Attempts to identify and quantify this strain have been limited to studies where the spectroscopic background of the protein is not overwhelming. Isotope effects are also sensitive to chances in vibrational frequencies, and consequently can detect electronic charge redistribution, and/or steric strain that is placed on a molecule. By measuring the binding isotope effect at equilibrium, strain in the lowest enzyme substrate complex will be detected. Being able to determine where strain is located in a substrate molecule will aid the design of improved inhibitors designed to relieve the strain but maintain the other essential binding features of the enzyme reactions. Carbanions of CoA thioesters are believed to be strained intermediates in a wide range of biosynthetic and fatty acid metabolizing enzymes. Inhibitors and inactivators of these enzymes have diverse bioactivities, ranging from antibiotics to hypocholesteremics. The mechanistic information available on the existence of these intermediates and on the factors promoting stabilization of the enzyme bound intermediates is unknown. Dithioesters of can provide a spectroscopic probe, both ultraviolet and resonance Raman, of that nature of the intermediates and the ability of this class of enzymes to strain these substrates. Alpha-Halo CoA dithioesters are more reactive than the alpha- halothioester analogs that can potentially alkylate the enzymatic general base that promotes ionization of the CoA esters. These novel reagants will be useful in mechanistic studies of the carbanion forming enzymes and as extremely potent inhibitors or inactivators may prove to be useful pharmaceutical, themselves.